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A Study of Risdiplam (RO7034067) in Adult and Pediatric Participants With Spinal Muscular Atrophy (Jewelfish)

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ClinicalTrials.gov Identifier: NCT03032172
Recruitment Status : Recruiting
First Posted : January 26, 2017
Last Update Posted : September 27, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE January 24, 2017
First Posted Date  ICMJE January 26, 2017
Last Update Posted Date September 27, 2019
Actual Study Start Date  ICMJE March 3, 2017
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
  • Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events Scale, V 4.0 [ Time Frame: Baseline up to 5 years ]
  • Percentage of Participants With Emergence or Worsening of Symptoms As Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) (Adult Version for Adults and Adolescents, Pediatric Version for Patients Aged 6-11 Years) [ Time Frame: Aged 6 to 60 Years: Screening, Day-1, Day 182, 364, 546, 728, at extension phase and follow-up visit 1 (Week 112) ]
  • Percentage of Participants With Protocol Defined Clinically Significant Changes in Ophthalmological Assessments [ Time Frame: Baseline up to 5 years ]
  • Percentage of Participants With Protocol Defined Clinically Significant Changes in Neurological Assessments [ Time Frame: Baseline up to 5 years ]
  • Tanner Staging Among all Participants Aged From 9 to 17 Years [ Time Frame: Baseline up to 5 years ]
  • Mean Plasma Concentration of RO7034067 [ Time Frame: Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during extension phase, at early withdrawal; Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, at early withdrawal and at follow-up visit 1 ]
  • Maximum Plasma Concentration (Cmax) of RO7034067 [ Time Frame: Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during extension phase, at early withdrawal; Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, at early withdrawal and at follow-up visit 1 ]
  • Area Under the Plasma Concentration Versus Curve (AUC) of RO7034067 [ Time Frame: Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during extension phase, at early withdrawal; Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, at early withdrawal and at follow-up visit 1 ]
  • Concentration of RO7034067 at the End of Dosing Interval (Ctrough) [ Time Frame: Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during extension phase, at early withdrawal; Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, at early withdrawal and at follow-up visit 1 ]
  • Mean Plasma Concentration of RO7034067 Metabolite [ Time Frame: Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during extension phase, at early withdrawal; Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, at early withdrawal and at follow-up visit 1 ]
  • Cmax of RO7034067 Metabolite [ Time Frame: Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during extension phase, at early withdrawal; Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, at early withdrawal and at follow-up visit 1 ]
  • AUC of RO7034067 Metabolite [ Time Frame: Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during extension phase, at early withdrawal; Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, at early withdrawal and at follow-up visit 1 ]
  • Ctrough of RO7034067 Metabolite [ Time Frame: Aged 6 month to 2 Years: Days 1, 14, 28, 91, 182, 273,364, 456, 546, 637, 728, every 26 weeks during extension phase, at early withdrawal; Aged 2 to 60 Years: Days 1, 14, 28, 91, 183, 273, 365, 456, 637, 729, at early withdrawal and at follow-up visit 1 ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 24, 2017)
  • Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) [ Time Frame: From screening up to 160 weeks ]
  • Percentage of Participants With Suicidal Ideation or Behavior, As Assessed Using Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline up to 104 weeks (assessed at baseline [Day1]; Days 119, 182, 364, 546, 728; early withdrawal visit [up to Week 104]) ]
  • Percentage of Participants With Protocol Defined Clinically Significant Changes in Ophthalmological Assessments [ Time Frame: Baseline up to 104 weeks (assessed at Weeks 8, 17, 26, 35, 43, 52, 61, 70, 78, 87, 96, 104; early withdrawal visit [up to Week 104]) ]
  • Tanner Staging Among all Participants Aged From 12 to 17 Years [ Time Frame: Month 24 ]
  • Mean Plasma Concentration of RO7034067 [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
  • Maximum Plasma Concentration (Cmax) of RO7034067 [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
  • Area Under the Plasma Concentration Versus Curve (AUC) of RO7034067 [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
  • Concentration of RO7034067 at the End of Dosing Interval (Ctrough) [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
  • Mean Plasma Concentration of RO7034067 Metabolite [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
  • Cmax of RO7034067 Metabolite [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
  • AUC of RO7034067 Metabolite [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
  • Ctrough of RO7034067 Metabolite [ Time Frame: 1, 2, 4, 6 hrs postdose on Days 1, 28, 56, 365, 609; predose (0 hr) on Days 7, 14, 28, 56, 119, 183, 245, 301, 365, 490, 609; Day 729; early withdrawal visit (up to Week 104); FU visit 1 (Week 112) ]
Change History Complete list of historical versions of study NCT03032172 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
  • SMN messenger Ribonucleic Acid (mRNA) Level in Blood [ Time Frame: Aged 2 to 60 Years: Days -1, 1, 28, 91, 183, 365, 729, at early withdrawal, and at follow-up visit 1; Participants Aged 6 Months to <2 Years: Day 1, 28, 182, 364 and 728 and at early withdrawal ]
  • SMN Protein Levels in Blood [ Time Frame: Aged 2 to 60 Years: Day -1, Day 28, 91, 183, 365, 729, at early withdrawal, and at follow-up visit 1; Participants Aged 6 Months to <2 Years: Day 1, 28, 182, 364 and 728 and at early withdrawal ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2017)
  • SMN messenger Ribonucleic Acid (mRNA) Level in Blood [ Time Frame: Day -1; predose (0 hr) on Days 7, 14, 183; 4 hr postdose on Days 1, 28, 365; Day 729; early withdrawal visit (up to Week 104); follow-up visit 1 (Week 112) ]
  • SMN Protein Levels in Blood [ Time Frame: Day -1; predose (0 hr) on Days 7, 14, 183; 4 hr postdose on Days 28, 365; Day 729; early withdrawal visit (up to Week 104); follow-up visit 1 (Week 112) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Risdiplam (RO7034067) in Adult and Pediatric Participants With Spinal Muscular Atrophy
Official Title  ICMJE An Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of RO7034067 in Adult and Pediatric Patients With Spinal Muscular Atrophy
Brief Summary This is a multi-center, exploratory, non-comparative, and open-label study to investigate the safety, tolerability, PK, and PK/PD relationship of risdiplam in adults, children and infants with Spinal Muscular Atrophy (SMA) previously enrolled in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previously treated with nusinersen, olesoxime or AVXS-101.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Spinal Muscular Atrophy
Intervention  ICMJE Drug: Risdiplam
Risdiplam will be administered orally once daily.
Other Name: RO7034067
Study Arms  ICMJE Experimental: Risdiplam
Participants will receive multiple doses of risdiplam orally once daily for 24 months. After 24-month treatment, participants will be offered the opportunity to enter the open-label extension (OLE) phase.
Intervention: Drug: Risdiplam
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 30, 2019)
180
Original Estimated Enrollment  ICMJE
 (submitted: January 24, 2017)
24
Estimated Study Completion Date  ICMJE December 27, 2024
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Confirmed diagnosis of 5q-autosomal recessive SMA
  • Previous enrollment in Study BP29420 (Moonfish) with the splicing modifier RO6885247 or previous treatment with any of the following: 1.) Nusinersen (defined as having received >= 4 doses of nusinersen, provided that the last dose was received >= 90 days prior to screening) or 2.) Olesoxime (provided that the last dose was received <= 18 months and >= 90 days prior to screening) or 3.) AVXS-101 (provided that the time of treatment was >= 12 months prior to screening)
  • Adequately recovered from any acute illness at the time of screening and considered well enough to participate in the opinion of the Investigator
  • For women of childbearing potential: negative blood pregnancy test at screening, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm
  • For patients aged 2 years or younger at screening: 1.) Parent or caregiver of patient is willing to consider nasogastric, naso-jejunal or gastrostomy tube placement, as recommended by the Investigator, during the study (if not already in place at the time of screening) to maintain safe hydration, nutrition and treatment delivery. 2.) Parent or caregiver of patient is willing to consider the use of non-invasive ventilation, as recommended by the Investigator during the study (if not already in place at the time of screening).

Exclusion Criteria:

  • Inability to meet study requirements
  • Concomitant participation in any investigational drug or device study
  • With the exception of studies of olesoxime, AVXS-101, or nusinersen: Previous participation in any investigational drug or device study within 90 days prior to screening, or 5 half-lives of the drug, whichever is longer
  • Any history of gene or cell therapy, with the exception of AVXS-101
  • Unstable gastrointestinal, renal, hepatic, endocrine, or cardiovascular system diseases as considered to be clinically significant by the Investigator
  • Inadequate venous or capillary blood access for the study procedures, in the opinion of the Investigator
  • For patients aged < 2 years, hospitalization for a pulmonary event within 2 months prior to screening and pulmonary function not fully recovered at the time of screening
  • Lactating women
  • Suspicion of regular consumption of drugs of abuse
  • For adults and adolescents only, positive urine test for drugs of abuse or alcohol at screening or Day -1 visit
  • Presence of clinically significant electrocardiogram (ECG) abnormalities before study drug administration from average of triplicate measurement or cardiovascular disease
  • For patients aged > 6 years, significant risk for suicidal behavior, in the opinion of the Investigator as assessed by the C-SSRS
  • Any major illness within one month before the screening examination or any febrile illness within one week prior to screening and up to first dose administration
  • Recently initiated treatment for spinal muscular atrophy (within 6 weeks prior to enrollment) with oral salbutamol or another beta 2-adrenergic agonist taken orally
  • Any prior use of chloroquine, hydroxychloroquine, retigabin, vigabatrin or thioridazine, is not allowed
  • Ascertained or presumptive hypersensitivity (e.g., anaphylactic reaction) to RO7034067 or to the constituents of its formulation - Concomitant disease or condition that could interfere with, or treatment of which might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the participant in this study
  • Recent history (less than one year) of ophthalmological diseases that would interfere with the conduct of the study as assessed by an ophthalmologist. Participants in whom Organic Cation Transporter or Spectral Domain-Optical Coherence Tomography (SD-OCT) measurement of sufficient quality cannot be obtained at screening will not be enrolled
  • Any prior use of an inhibitor or inducer of FMO1 or FMO3 taken within 2 weeks (or within 5 elimination half-lives, whichever is longer) prior to dosing
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 60 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: BP39054 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com
Listed Location Countries  ICMJE Belgium,   France,   Germany,   Italy,   Netherlands,   Poland,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03032172
Other Study ID Numbers  ICMJE BP39054
2016-004184-39 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP